During the period 01 Oct 06 to 30 Sept 07, significant progress was made on this research project. During said reporting period, we studied the effects of AM251, a novel highly selective cannabinoid CB1 receptor antagonist, on cocaine-triggered relapse to drug-seeking behavior using the reinstatement animal model and on cocaine-induced changes in extracellular dopamine, glutamate, and gamma-aminobutyric acid (GABA) under reinstatement conditions. We found that systemic administration of AM251 selectively inhibited cocaine-induced, but not sucrose plus sucrose cue-induced, reinstatement of reward-seeking behavior. AM251 alone did not trigger reinstatement. Local micro-perfusion of AM251 into the nucleus accumbens of the limbic forebrain or the dorsal striatum also inhibited cocaine-triggered reinstatement. AM251 alone dose-dependently elevated nucleus accumbens glutamate in a voltage-dependent sodium-channel-dependent manner. AM251 did not affect nucleus accumbens dopamine or GABA. Pretreatment with AM251 dose-dependently inhibited cocaine-induced increases in nucleus accumbens glutamate but not in dopamine. Blockade of nucleus accumbens metabotropic glutamate mGluR2/3 receptors by LY341495 slightly facilitated cocaine-enhanced glutamate release but blocked the antagonism of cocaine-triggered reinstatement by AM251. We conclude that: 1) CB1 cannabinoid receptors exert tonic inhibition over nucleus accumbens glutamate release under cocaine-extinction conditions; 2) blockade of CB1 cannabinoid receptors by AM251 inhibits cocaine-enhanced nucleus accumbens glutamate release and cocaine-triggered reinstatement; and 3) these effects appear to be mediated by activation of presynaptic mGluR2/3 autoreceptors secondary to AM251-induced increase (disinhibition) of nucleus accumbens glutamate release. We further found that AM251 dose-dependently lowered (by 30-70%) the break-point for intravenous cocaine self-administration under progressive-ratio reinforcement conditions in laboratory rats. Administration of the CB1 receptor antagonist SR141716 lowered the break-point by 35%, which did not reach statistical significance. Neither AM251 nor SR141716 altered cocaine self-administration under fixed-ratio (FR2) reinforcement conditions. AM251 also significantly and dose-dependently inhibited (by 25-90%) cocaine-enhanced brain stimulation reward, while SR141716 attenuated cocaine's reward-enhancing effect only at the highest dose of SR141716 tested and only producing a 40% attenuation. AM251 alone, at all doses tested, had no effect on brain stimulation reward, while high doses of SR141716 alone significantly inhibited brain reward. These data suggest that blockade of CB1 receptors by AM251 dose-dependently inhibits cocaine's rewarding effects (as assessed by both progressive-ratio intravenous cocaine self-administration and by electrical brain stimulation reward), whereas SR141716 is largely ineffective. We believe that the inhibition of brain reward produced by high doses of SR141716 may underlie clinical reports of dysphoria and/or depression in humans treated with SR141716. We conclude that AM251 or other more potent and selective CB1 cannabinoid receptor antagonists deserve further study as potentially effective anti-cocaine medications.